1. Field of the Invention
The present invention relates to a composition for the prevention and treatment of NSCLC (non-small cell lung cancer), comprising a pyrazino-triazine derivative.
2. Description of the Related Art
Primary lung cancer, which originates from the lung as implied by the term, is classified largely into small cell lung cancer and non-small cell lung cancer (NSCLC) according to histological type. Accounting for more than 80% of lung cancers, NSCLC is the highest cause of cancer-related death in the U.S.A, with a cure rate of less than 15% and an average survival period of 8˜10 months. Once the cancer has progressed beyond the early stages, no surgical approaches are allowed, and the only resort is chemotherapy. However, NSCLC has poor sensitivity to anticancer agents because it is highly heterogeneous, consisting of different cell types.
For this reason, the doublet therapy of cytotoxic drugs is predominantly used to treat NSCLC. Among the cytotoxic drugs used for double therapy for NSCLC are carboplatin, paclitaxel, docetaxel and etoposide, with the preferential combination being paclitaxel and carboplatin. In addition, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), a targeted therapeutic which inhibits epidermal growth factor (EGF), is commercially available under the brand names of Tarceva® and Irresa® as drugs for NSCLC.
Causing significant toxicity, the doublet therapy of those cytotoxic drugs is limitedly applied to patients who are physically weak, such as senile patients. In addition, this therapy can neither guarantee good anticancer efficiency nor a low recurrence rate for NSCLC patients in a very early or an advanced phase. Hence, there is a need for a newly established chemotherapy regimen targeting NSCLC centering on therapeutically excellent and non-toxic anticancer agents.
Targeted therapeutics, such as EGFR TKI, are applicable only to cancer patients who express specific target factors. For example, a clinical report has it that Tarceva® or Irresa® has high therapeutic effects particularly for some of the patients having a mutation on the epidermal growth factor receptor (active EGFR mutation (L858R, delE746_A750)), compared to patients having wild-type (WT) EGFR. This clinical response is attributable to the increased binding affinity of EGFR TKI for the mutated EGFR (Science Vol. 304, 4, Jun. 2004). However, in spite of the excellent anticancer activity of EGFR TKI on patients with the active mutation, many of the patients treated with EGFR TKI in 2005 have relapsed into chemoresistance to EGFR TKI, and an epigenetic analysis showed that the gatekeeper amino acid in EGFR TKI, threonine 790, is changed into methionine (T790M) in 50% of the relapsed patients (FIGS. 1 and 2). Crystallographic analysis shows that T790M mutation causes drug resistance by decreasing of binding affinity due to the steric hindrance at the binding position between Tarceva® and the methionine residue (NEJM Vol. 352, 8, Feb. 2005). In addition to the T790M mutation, other mutations including L747S, D761Y and T854A were also reported, but account for less than 10% of the relapses and thus are less important (Nature reviews cancer Vol. 10, 2010). There is insufficient data about which therapy is suitable for NSCLC patients having both the activation mutation and T790M (exon 20) (British Journal of Cancer 105(1), 1-8, 2011).
There is therefore a need for an agent that exhibits an excellent therapeutic effect on NSCLC in patients having an active mutation on EGFR as well as patients having WT EGFR and for patients relapsed into chemoresistance to EGFR TKI.
Meanwhile, WO12/050393, WO10/120112, WO09/05197 and WO09/148,192 disclose a number of compounds in the form of pyrazino-triazine derivatives which show anticancer activity. The therapeutic effects that the compounds mentioned above have on NSCLC is nowhere mentioned in the prior art documents. Among them, the compound derivatives represented by Chemical Formula 1 were surprisingly found by the present inventors to have therapeutic effects on NSCLC resistant to EGFR TKI.